synthesis and catalytic functionalization of biologically active indoles

le to isolate the pyridazinone derivatives 3a–h directly in moderate
to good yields (Table 2). For example, reaction of p-tolylhydrazine
proceeded over both steps in 61% yield (Table 2, entry 2),
while the more sterical hindered o-tolylhydrazine gave a lower
yield of 47% (Table 2, entry 3). Compared to the p-tolyl-substituted
pyridazinone a similar yield is observed for the p-isopropyl-substituted
pyridazinone derivative with 64% yield (Table 2, entry 4).
Besides alkyl-substituted arylhydrazines, we also tested phenylhydrazines
with electron-withdrawing substituents. These methylsulfonyl-,
cyano-, and 4-bromophenyl-substituted pyridazinones
are synthesized in up to 71% yield (Table 2, entries 5–7). In addition,
the 3,4-dichloro-substituted phenylhydrazine in para- and
meta-position gave the corresponding pyridazinone 3h in 57% yield
(Table 2, entry 8).
In conclusion, we have developed a novel method for the synthesis
of aryl-substituted 4,5-dihydro-3(2H)-pyridazinones based
on domino hydrohydrazination and condensation reactions. Eight
substituted arylhydrazines react with 4-pentynoic acid in the presence
of ZnCl2 to give the corresponding pyridazinone derivatives in
a one-pot process in moderate to good yields. Notably, this convenient
and practical procedure does not require any special handling,
unusual reagents, and proceeds without the exclusion of
air or water.
Acknowledgments
This work has been funded by the State of Mecklenburg-Western
Pomerania, the BMBF (Bundesministerium für Bildung und
Forschung), the Deutsche Forschungsgemeinschaft (Graduiertenkolleg
1213, and Leibniz-price), and the Fonds der Chemischen
Industrie (FCI). We thank Dr. W. Baumann, Dr. C. Fischer, S. Buchholz,
S. Schareina, and K. Mevius for their excellent technical and
analytical support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.084.
References and notes
1. (a) Mitchinson, A.; Blackaby, W. P.; Bourrain, S.; Carling, R. W.; Lewis, R. T.
Tetrahedron Lett. 2006, 47, 2257–2260; Review (b) Lee, S.-G.; Kim, J.-J.; Kim,
H.-K.; Kweon, D.-H.; Kang, Y.-J.; Cho, S.-D.; Kim, S.-K.; Yoon, Y.-J. Curr. Org.
Chem. 2004, 8, 1463–1480; (c) Byth, K. F.; Cooper, N.; Culshaw, J. D.; Heaton, D.
W.; Oajes, S. F.; Minshull, C. A.; Norman, R. A.; Pauptit, R. A.; Tucker, J. A.; Breed,
J.; Pannifer, A.; Roswell, S.; Slanway, J. J.; Valentine, A. L.; Thomas, A. P. Bioorg.
K. Alex et al. / Tetrahedron Letters 49 (2008) 4607–4609 4609
Med. Chem. Lett. 2004, 14, 2249–2252; (d) Velentza, A. V.; Wainwright, M. S.;
Zadadzki, M.; Mirzoeva, S.; Schumacher, M.; Haiech, J.; Focia, P. J.; Egli, M.;
Waterson, D. M. Bioorg. Med. Chem. Lett. 2003, 13, 3465–3470; (e) Contreras, J.
M.; Parrot, I.; Sippl, W.; Rival, Y. M.; Wermuth, C. G. J. Med. Chem. 2001, 44,
2707–2718; (f) Katritzky, A. R.; Pleynet, D. P. M.; Yang, B.; Yao, J. Synthesis 1998,
1627–1630. and references therein; Review (g) Matyus, P. J. Heterocycl. Chem.
1998, 35, 1075–1089; (h) Coates, W. J. Pyridazines and Their Benzo Derivatives.
In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 6, p 191.
2. Estevez, I.; Ravina, E.; Sotelo, E. J. Heterocycl. Chem. 1998, 35, 1421–1428. and
references therein.
3. (a) Sircar, I.; Duell, B. L.; Bobowski, G.; Bristol, J. A.; Evans, D. B. J. Med. Chem.
1985, 28, 1405–1413; (b) Bristol, J. A. J. Med. Chem. 1984, 27, 1099–1101.
4. (a) Campos, K. R.; Woo, J. C. S.; Lee, S.; Tillyer, R. D. Org. Lett. 2004, 6, 79–82; (b)
Gouault, N.; Cupif, J. F.; Picard, S.; Lecat, A.; David, M. J. Pharm. Pharmacol. 2001,
53, 981–985; (c) Ege, S. N.; Carter, M. L. C.; Ortwine, D. F.; Chou, S.-S. P.;
Richman, J. F. J. Chem. Soc., Perkin Trans. 1 1977, 1252–1257; (d) Wamhoff, H.;
Korte, F. Liebigs Ann. Chem. 1969, 724, 217–220; (e) Stevens, F. J.; Griffin, T. D.;
Fields, T. L. J. Am. Chem. Soc. 1955, 77, 42–44.
5. Fischer, E. Liebigs Ann. Chem. 1886, 236, 126–151.
6. Recent selected examples: (a) Murphy, D. E.; Dragovich, P. S.; Ayida, B. K.;
Bertolini, T. M.; Li, L.-S.; Ruebsam, F.; Stankovic, N. S.; Sun, Z.; Zhao, J.; Zhou, Y.
Tetrahedron Lett. 2008, 49, 811–815; (b) Mohamed, N. R.; El-Saidi, M. M. T.; Ali,
Y. M.; Elnagdi, M. H. J. Heterocycl. Chem. 2007, 44, 1333–1337; (c) de Araujo-
Junior, J. X.; Schmitt, M.; Antheaume, C.; Bourguignon, J.-J. Tetrahedron Lett.
2007, 48, 7817–7820; (d) Helm, M. D.; Plant, A.; Harrity, J. P. A. Org. Biomol.
Chem. 2006, 4, 4278–4280.
7. (a) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. ChemSusChem 2008, 1, 333–
338; (b) Tillack, A.; Khedkar, V.; Jiao, H.; Beller, M. Eur. J. Org. Chem. 2005,
5001–5012; (c) Tillack, A.; Khedkar, V.; Beller, M. Tetrahedron Lett. 2004,
45, 8875–8878; (d) Khedkar, V.; Tillack, A.; Beller, M. Org. Lett. 2003, 5,
4767–4770; (e) Tillack, A.; Garcia Castro, I.; Hartung, C. G.; Beller, M.
Angew. Chem. 2002, 114, 2646–2648; . Angew. Chem., Int. Ed. 2002, 41,
2541–2543.
8. Selected recent reviews on hydroaminations of alkynes: (a) Severin, R.; Doye, S.
Chem. Soc. Rev. 2007, 36, 1407–1420; (b) Lee, A. V.; Schafer, L. L. Eur. J. Inorg.
Chem. 2007, 2243–2255; (c) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev.
2004, 104, 3079–3159.
9. (a) Alex, K.; Schwarz, N.; Khedkar, V.; Sayyed, I. A.; Tillack, A.; Michalik, D.;
Holenz, J.; Diaz, J. L.; Beller, M. Org. Biomol. Chem. 2008, 6, 1802–1807; (b)
Sayyed, I. A.; Alex, K.; Tillack, A.; Schwarz, N.; Spannenberg, A.; Michalik, D.;
Beller, M. Tetrahedron 2008, 64, 4590–4595; (c) Schwarz, N.; Alex, K.; Sayyed, I.
A.; Khedkar, V.; Tillack, A.; Beller, M. Synlett 2007, 1091–1095; (d) Sayyed, I. A.;
Alex, K.; Tillack, A.; Schwarz, N.; Michalik, D.; Beller, M. Eur. J. Org. Chem. 2007,
4525–4528; (e) Khedkar, V.; Tillack, A.; Michalik, D.; Beller, M. Tetrahedron
2005, 61, 7622–7631; (f) Tillack, A.; Jiao, H.; Garcia Castro, I.; Hartung, C. G.;
Beller, M. Chem. Eur. J. 2004, 10, 2409–2420; (g) Khedkar, V.; Tillack, A.;
Michalik, M.; Beller, M. Tetrahedron Lett. 2004, 45, 3123–3126.
10. (a) Banerjee, S.; Barnea, E.; Odom, A. L. Organometallics 2008, 27, 1005–1014;
(b) Ackermann, L.; Born, R. Tetrahedron Lett. 2004, 45, 9541–9544; (c) Cao, C.;
Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853–2856; (d) Walsh, P. T.; Carney, M. J.;
Bergman, R. G. J. Am. Chem. Soc. 1991, 113, 6343–6345.
11. Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Org. Lett., in press.
12. (a) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Angew. Chem. 2008, 120, 2337–
2340; Angew. Chem., Int. Ed. 2008, 47, 2304–2307.
13. For a recent review on Markovnikov and anti-Markovnikov functionalization of
olefins and alkynes, see: (a) Seayad, J.; Tillack, A.; Jiao, H.; Beller, M. Angew.
Chem. 2004, 116, 3448–3479; Angew. Chem., Int. Ed. 2004, 43, 3368–3398.
14. For recent review in Friedel–Crafts acylation reaction, see: Sartori, G.; Maggi, R.
Chem. Rev. 2006, 106, 1077–1104.